The present disclosure relates to an optimised system for aseptically culturing cells for therapeutic applications on a commercially viable scale, methods of manufacturing said systems and methods of using the systems to manufacture cellular therapeutics.
WO 2005/035728 describes a system with a gas permeable portion for culturing cells. This device is available from Wilson Wolf under the brand G-Rex Technology (please see the website www.wilsonwolf.com/page/show/67596). The main benefit of the system is that it allows nutrients and gases to be provided to growing cells in a way so that the cells can be continuously grown for periods of up to 14 days without any further intervention, in particular: the gas permeable membrane allows exchange of CO2 and O2 and the arrangement allows large volumes of media to be employed which provides all the nutrients necessary for growth. The arrangement is shown in FIG. 1.
The main limitation of the G-Rex technology is that it is an open manufacturing system that does not allow the inoculation and harvesting of cells and addition of nutrients without exposure to the external environment. Since cellular therapeutics cannot be sterilised post production, their manufacture has to occur under aseptic conditions. Thus the “open” processing steps during which the product is exposed to the external environment have to be performed under a laminar air flow cabinet which is operated in a clean-room classified according to EU-GMP classification class B (US Fed. Std. 209e class 10,000, ISO 14644-1 class ISO7) to prevent contamination of the product with microbes and particles. Facilities with such clean-room technology, for open processing, are expensive to build, operate, maintain and monitor.
Equally important is the fact that the open operation steps require that only one product can be handled at a time in the same clean-room space to minimise the risk of cross-contamination, hence, the product throughput is limited and this manufacturing system requires multiple clean-rooms and production teams to operate in parallel to achieve high volumes of production output. For small and medium size companies as well as hospitals, the capital investment and labour costs are very significant on a per unit basis of production.
To address this problem the present inventors have provided a modified system for the culture of cells that allows aseptic manufacturing of cells for use in therapy, without the need for a clean-room environment because no open processing steps are required.